ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4046C>T (p.Thr1349Met) (rs80357345)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077561 SCV000244352 benign Breast-ovarian cancer, familial 1 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000442
Invitae RCV000195392 SCV000076435 likely benign not provided 2019-02-18 criteria provided, single submitter clinical testing
GeneDx RCV000048422 SCV000209966 likely benign not specified 2017-07-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162981 SCV000213469 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000048422 SCV000591483 uncertain significance not specified 2012-02-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048422 SCV000699102 likely benign not specified 2019-04-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4046C>T (p.Thr1349Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 301778 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4046C>T has been reported in the literature in individual(s) from hereditary breast/ovarian cancer families (Judkins_2005) and an individual affected with Medulloblastoma who also carried a pathogenic variant in the APC gene (c.2805C>G, p.Y935*) (Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been reported in the FLOSSIES database in one woman older than age 70 years who has never had cancer while, it was also reported by Momozawa et al (2018) in one control 60 years old or over with no past history nor family history of cancers; these data provide supporting evidence for a benign role of the variant. Furthermore, databases (LOVD, UMD) and peer-reviewed studies (Momozawa_2018, Zhang_2015, Easton_2007) classify this variant as likely benign/benign/neutral. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign while, a submission from an expert panel (ENIGMA) cites the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000162981 SCV000912032 likely benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077561 SCV000109363 uncertain significance Breast-ovarian cancer, familial 1 2007-12-11 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077561 SCV000144946 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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